An interaction between the immune system and the brain causes important behavioral changes. Sickness behavior is induced by a transient episode of pro-inflammatory cytokine expression in the brain. If unabated, the chronic inflammatory response can ultimately lead to development of depressive-like behavior. We recently discovered that insulin-like growth factor-I (IGF-I), a hormone that is critical for growth and development and whose endogenous-tonic presence is neuroprotective, inhibits sickness behavior when given either centrally (icv.) or peripherally (i.p.). We now have exciting new preliminary data showing that the in vivo action of IGF-I is mimicked by the naturally occurring N-terminal tripeptide of mature IGF-I, GPE. This application is based on the premise that processing of IGF-I, resulting in GPE and des-(1-3)-IGF-I, provides the brain with two biologically active peptides that both work to protect central function. Successful completion of four objectives will allow us to define the anti-inflammatory role of GPE and des-(1-3)-IGF-I within the CNS. Objective 1 will characterize the ability of supplemental GPE alone or with des-(1-3)-IGF-I, both given icv, to block both sickness and depressive-like behaviors. This model mimics the ability of exercise to elevate IGF-I in the brain. Peripherally-initiated inflammatory episodes, initiated by lipopolysaccharide given i.p., will be used to induce brain cytokine expression and signaling. Transient sickness behavior will be quantified using well established measures of sickness. Depressive-like behavior will be determined after mice have recovered from sickness behavior using two already validated end-points. Objective 2 is critical as it will determine the mode of action by which GPE and des-(1-3)-IGF-I act within the brain to prevent pro-inflammatory cytokine-dependent behavioral changes. Pro-inflammatory and anti-inflammatory cytokine production, as well as pro-inflammatory cytokine signaling, will be quantified following icv. treatment with GPE or des-(1-3)-IGF-I to test our hypothesis that these two peptides use distinct mechanisms within the brain to block sickness and depressive-like behaviors. Objective 3 will use in vitro models to clearly determine the cell(s) within the central nervous system that bind and respond to des-(1-3)-IGF-I and GPE. The fourth and last objective will use in vitro and ex vivo models to define the mechanisms involved in the central responses elicited by des-(1-3)-IGF-I and GPE to antagonize an inflammatory episode. The responses of the three major cell types of the CNS (neurons, microglia and astrocytes) and ex vivo organotypic slice cultures will be compared to confirm that the modus operandi of GPE and des-(1-3)-IGF-I that are utilized in vivo can be modeled in controlled systems. Techniques that are needed to successfully complete these objectives have been developed. Experiments in this application are critical to understand how a major endogenous hormone, that until now has been known mainly for its growth promoting actions, functions in the brain to antagonize clinically-important behaviors that occur during inflammation. PUBLIC HEALTH RELEVANCE Our recent discovery that the interaction between the brain and an activated immune system can be regulated by a natural fragment of IGF-I, GPE, opens a new window of opportunity to define how the IGF system acts to reduce sickness and depressive-like behaviors. With the potential to diminish the negative impact of pro-inflammatory cytokines in the brain, the IGF system has independently been shown to decrease a variety of cytokine-dependent psychopathologies, including cognitive dysfunction, chronic pain, depression, and sickness behavior. A major strength of this application is the use of a multidisciplinary approach to integrate the fields of immunology, behavior and endocrinology to learn how a physiologically-relevant growth factor and cytokines interact to maintain and promote function of the brain and increase quality of life.